三转基因老年痴呆模型小鼠的生物节律特征及机制研究

Alzheimer's disease (AD) is one of the most common form of dementia among the elderly, which is severely impaired the health and lifetime of old persons. In addition to progressive impairment of memory and cognitive performance, alteration of circadian rhythm and sleep pattern is one of the most common symptoms in Alzheimer patients. In mammals, sleep schedule and circadian variation of many phsiological functions are regulated by a circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. AD patients tend to doze off during the day but wonder around the house at night. The increased daytime sleepiness worsens cognitive performance, while the fragmented nocturnal sleep further impairs memory consolidation during sleep and other symptoms in AD. Although the exact neuropathogenesis of AD remains unknown, neuritic plaques and neurofibrillary tangles are pathological hallmarks in the postmortem brain. The triple-transgenic (3xTg-AD) mouse, which is one of the best animal models of AD, expresses all three genes associated with familial AD and exhibits both amyloid plaques and neurofibrillary tangles in a comparable manner to that observed in AD patients. Recently, part of the behavioral abnormality in circadian rhythmicity of the 3xTg-AD mice was reported, but the whole characterization and the mechanism are still not clear. We propose to investigate the alteration of circadian rhythm of the 3xTg-AD mice both in vivo and in vitro with wheel running activity analysis and the SCN brain slice electrophysiological recording, respectively. In addition, we will investigate circadian clock expression profile with real time PCR. Thus, our project will provide further insight into the cell and molecular mechanism underlying the alteration of circadian rhythm associated with AD, which may lead to the development of novel therapeutic avenues for prevention and treatment.

睡眠周期与生物节律的改变是阿尔茨海默病（Alzheimer's disease, AD）最常见的临床症状之一。在哺乳类动物，睡眠周期与机体各种生理功能的生物节律由下丘脑的视交叉上核（suprachiasmatic nucleus, SCN）调节，生物节律紊乱及其所导致的多种生理功能的紊乱会影响学习记忆功能，并进一步恶化AD症状。三转基因AD模型小鼠（triple-transgenic model, 3xTg-AD）是一种能够表现AD主要病理特征，模拟AD病程的最佳动物模型。目前已有少量关于3xTg-AD模型小鼠生物节律改变的行为学研究，但对AD病程中生物节律改变的具体特征和机制仍不明确。本研究将采用跑轮活动行为学测试、SCN脑片细胞外单单位放电记录和实时定量PCR技术进一步探讨该模型小鼠生物节律变化的特征和可能的机制，从而为预防和治疗AD病程中的生物节律紊乱，减缓AD进程提供新的策略。

除学习记忆能力丧失以外，睡眠周期与生物节律的改变是阿尔茨海默病（Alzheimer's disease, AD）最常见的临床症状之一。在哺乳类动物，睡眠周期与机体各种生理功能的生物节律由下丘脑的视交叉上核（suprachiasmatic nucleus, SCN）调节，生物节律紊乱及其所导致的多种生理功能的紊乱会影响学习记忆功能，进一步恶化AD症状。三转基因AD模型小鼠（triple-transgenic model, 3xTg-AD）是一种能够表现AD主要病理特征，模拟AD病程的最佳动物模型。目前已有少量关于3xTg-AD小鼠模型生物节律改变的行为学研究，但具体特征和机制仍不明确。本研究采用跑轮活动行为学测试、SCN脑片细胞外单单位放电记录和实时定量PCR技术探讨该模型小鼠生物节律变化的特征和机制。. 研究结果发现，雌雄3xTg-AD小鼠均在3月龄时已经出现内源性的昼夜节律紊乱；6月龄时外源性和内源性昼夜节律均表现出一定程度的紊乱，且以雄性3xTg-AD小鼠的昼夜节律紊乱更为严重；9月龄时外源性和内源性昼夜节律均明显紊乱；此外，雌雄3xTg-AD小鼠均随月龄增加出现振幅明显下降和运动活性降低。同时，各月龄3xTg-AD小鼠的SCN神经元自发放电频率始终表现出明显的昼夜节律性，且放电频率峰值出现在ZT 7，但峰值放电频率随月龄增加逐步降低。PCR检测证实雌雄3xTg-AD小鼠均从3月龄开始即出现per1和per2表达峰值的延后，同时per1和per2基因表达量均随月龄增加呈下降趋势，且雄性小鼠下降较快。结合行为学、电生理和和分子生物学实验结果，我们推测3xTg-AD小鼠昼夜节律紊乱可能与SCN神经元放电频率及生物钟基因per1、per2表达改变有关。此外，3xTg-AD小鼠可能在早期就出现内源性昼夜节律紊乱，随月龄增加又逐渐表现出外源性昼夜节律紊乱，提示在临床上及早发现和治疗昼夜节律紊乱，可能为早期预防和治疗AD、减缓AD进程，提供新的策略。